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105 Review Neuromuscular Blockade in Children MAY-JUNE REV. HOSP. CLÍN. FAC. MED. S. PAULO 55(3):105-110, 2000 REVIEW NEUROMUSCULAR BLOCKADE IN CHILDREN João Fernando Lourenço de Almeida, W. Jorge Kalil Filho and Eduardo J. Troster RHCFAP/3012 ALMEIDA J F L de et al. - Neuromuscular blockade in children. Rev. Hosp. Clín. Fac. Med. S. Paulo 55(3):105-110, 2000. SUMMARY: Neuromuscular blocking agents (NMBAs) have been widely used to control patients who need to be immobilized for some kind of medical intervention, such as an invasive procedure or synchronism with mechanical ventilation. The purpose of this monograph is to review the pharmacology of the NMBAs, to compare the main differences between the neuromuscular junction in neonates, infants, toddlers and adults, and moreover to discuss their indications in critically ill pediatric patients. Continuous improvement of knowledge about NMBAs pharmacology, adverse effects, and the many other remaining unanswered questions about neuromuscular junction and neuromuscular blockade in children is essential for the correct use of these drugs. Therefore, the indication of these agents in pediatrics is determined with extreme judiciousness. Computorized (Medline 1990-2000) and active search of articles were the mechanisms used in this review. DESCRIPTORS: Neuromuscular blocking agents. Neuromuscular blocking drugs. Neuromuscular junction. Neuromuscular block. Neonate. Infant. Child. Since the introduction of the neu- NMBAs, and we also review the clini- romuscular junction contains some romuscular blocking agents (NMBAs) cal and pharmacologic advances of the types of nicotinic receptors: in 1942, a marked evolution has oc- new agents as well as their complica- • Two on the muscle surface; curred in these drugs, with progressive tions. •one junctional; increase in their potency combined • one extrajunctional; with fewer risks or adverse effects. Physiology of neuromuscular trans- • one presynaptic receptor on the Many of these NMBAs have appeared mission and blockade parasympathetic-nerve ending 5, 6. in the last 10 years, with an increase in The postsynaptic receptors are pro- their use in intensive care units1. On the Definition: The neuromuscular teins with five subunits: a , β, χ, δ e ∋. other hand, the development of new blockade can be defined as a reversible Each neuromuscular junction contains drugs has made the choice of agents interruption of neuromuscular trans- 1–10 million nicotinic receptors3, 4, 6. much more complex, due to differ- mission in the Acetylcholine (AcC) Physiology of neuromuscular trans- ences in pharmacology, clinical indica- nicotinic receptors, fin the absence of mission: The neuromuscular transmis- tions, and side effects of each new any analgesic, sedative or amnesic ac- sion initiates when a nerve impulse ar- drug2. The NMBAs have been rou- tion. In summary, the normal neuro- rives on the presynaptic nerve endings, tinely given to critically ill patients to muscular transmission is related to the with liberation of AcC molecules. The facilitate tracheal intubation, for stimulation of the postsynaptic junc- AcC-liberated molecule crosses the muscle relaxation during surgery (gen- tional receptors of AcC that arouse the junctional cleft to stimulate the erally abdominal and thorax surgery) depolarization and muscular contrac- postsynaptic receptors. and to patients who offer resistance to tion3, 4. Nicotinic Receptors: The neu- To begin the opening of the chan- mechanical ventilation (despite the use nel receptors, which allow the move- of intense analgesia and sedation). ment of ions that will finally depolar- From the Department of Pediatrics, Hospital In this review, we analyze the phar- das Clínicas, Faculty of Medicine, University ize the end plate, 2 AcC molecules macology of and indications for the old of São Paulo. must bind simultaneously to two a sub- 105 REV. HOSP. CLÍN. FAC. MED. S. PAULO 55(3):105-110, 2000 MAY-JUNE units of a postsynaptic receptor. When lar junction (NMJ) is still developing. makes the diaphragm of a infant more this happens, a brief opening (1 msec.) In this maturation phase, the receptors reactive to NMBAs than his own of the channel occurs, with a non-se- have an increased metabolic activity8. peripheric musculature3. lective passage of sodium and calcium The main point that distinguishes to the muscle, leading to depolarization the immature receptors from the devel- Classification of NMBAs of the muscular membrane and muscu- oped ones is a functional difference lar contraction. that occurs due to a prolonged open- The NMBAs are classified as fol- Then the AcC molecule is quickly ing of the ionic channels. This allows lows: broken down by the enzyme acetylcho- the immature muscles to be more eas- 1) Based on the pharmacologic linesterase in the junctional cleft, stop- ily depolarized, and these receptors mechanism: ping the muscular contraction6. have also a greater affinity for depolar- a. Depolarizing drugs; Physiology of the neuromuscular izing agents and lower affinity for b. Nondepolarizing drugs. blockade: The neuromuscular blockade nondepolarizing agents3, 5, 8, 9. 2) Based on the biochemical structure: can exist by two distinct mechanisms: One of the age-related particulari- a. Benzylisoquinolinium deriva- • Depolarizing neuromuscular block- ties is the alteration in the degree of tives; ade; neuromuscular blockade with the body b. Aminosteroids compounds. The neuromuscular blockade by the composition and the drug distribution. 3) Based on the duration of the de- classic pathway (depolarizing), be- Since the NMBAs distribute in the ex- sired effect: gins when a drug bind to the a sub- tracellular fluid exclusively, and since a. Short-acting drugs; unit of the nicotinic receptors like neonates and infants have a larger ex- b. Intermediate-acting drugs; the molecule of AcC does. In the tracellular compartment with a higher c. Long-acting drugs. beginning, an initial opening of the volume of distribution, neonates and ion channel produces a contraction infants require high doses of NMBAs The NMB drugs have many indica- (fasciculation). After this, the depo- to reach the desired effect. This differ- tions and adverse effects. For this rea- larization of muscular membrane is ence is decreased in toddlers and son, anaesthesiologists and intensivists sustained (persistent depolariza- school-aged children that have a vol- are trying to systematize the choice of tion), since the drug is not broken ume of distribution close to Adults (fig- the “ideal NMBA”, which has to: have by acetylcholinesterase, leading to ure 1)5. rapid onset of action and ease of rever- neuromuscular block. Concerning the alterations concern- sion; have low toxic levels; have few • Nondepolarizing neuromuscular ing the type of muscular fibers (type I, autonomic and cardiovascular effects; blockade; or slow-twitch, and type II, or fast- are metabolized and excreted indepen- In the nondepolarizing neuromus- twitch), it is important to note that the dently of the final organic function; cular blockade, the drugs bind in a type I fibers are more sensitive to and have low cost. competitive way (with AcC) to at NMBAs as compared to type II fibers. least one a subunit of the nicotinic Type I fibers have clinical relevance, Depolarizing agents (agonists) receptors. Since there is no biding since the diaphragm of a neonate has of at least two molecules of AcC, fewer type I fibers as compared to a Succinylcholine (Sch): Succinyl- there is no opening of the ion chan- diaphragm of a toddler or a adult. This choline is considered a nondepo- nels and no muscular depolariza- tion, with the muscle becoming flacid6, 7. Particularities of neuromuscular blockade in children There are some characteristic points in the neuromuscular junction that differentiate newborns and infants from other ages. In the first 2 months of life (in par- Figure 1 - Age-related changes in the steady state volume of distribution (Vd) da D-tubocurarine (curare) parallel maturational changes in the volume of the extracellular fluid space (Vlec). (Fisher et ticular the newborn), the neuromuscu- al.)5. 106 MAY-JUNE REV. HOSP. CLÍN. FAC. MED. S. PAULO 55(3):105-110, 2000 larizing NMBA with short action and 2) Prolonged neuromuscular blockade action as rapid as succinylcholine, with is the only nondepolarizing agent avail- (plasma cholinesterase deficiency); decreased duration as compared to able for clinical use today. Due to its 3) Cardiovascular effects (dysrhythmias mivacurium. Recent studies show a fast initial action, the main indication – generally bradyarrhythmias in chil- similar effect in children, with little of this drug is for tracheal intubation dren, with recommendation to dispose cardiovascular effects and histamine (considered the first choice in recent of atropine for immediate use); release16. review)10. Succinylcholine (Sch) is 4) Anaphylaxis; formed by 2 joined AcC molecules and 5) Myoglobinemia and myoglobinuria; Intermediate action rapidly hydrolyzes into succinic acid 6) Hyperkalemia; and choline by the (pseudo) cholinest- 7) Malignant hyperthermia (associated Atracurium: Atracurium is a erase in patients with normal levels of with inhalation anesthetics)11, 12, 13. bisquaternary intermediate NMBA (an this enzyme. ammonium benzylisoquinolinium). It Succinylcholine acts by stimulation Nondepolarizing agents (antagonists) has an onset of action of 2 minutes of the cholinergic receptors (activation with a peak in 5 to 10 minutes. Its du- of the NM junction) that leads to de- Short action ration is about 40 to 60
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